This project investigates the neurobehavioral effects of ingested aluminum (Al). It seeks to clarify potential human health risks associated with ingestion of Al in food, water and pharmaceuticals. Brain Al accumulation and changes in neurobehavioral indices have been described after dietary exposure to Al in both adult and developing mice. Data from the last project period point to oligodendrocytes as a CNS cell type particularly sensitive to Al, and myelination as a process disrupted by Al exposure. Al, like Fe, can be taken up by oligodendrocytes via transferrin receptors. The investigator hypothesizes that Al interferes with Fe uptake of oligodendrocytes during the critical period of developmental myelination, and that, in adults, Al in oligodendrocytes becomes localized in myelin where it promotes oxidative damage and myelin loss. Specific Aim 1 examines the basis of reduced Fe uptake in Al exposed oligodendrocytes. Downregulation of surface transferrin receptors in oligodendrocytes demonstrated in the last project period, could be due to altered receptor recycling rates or a decrease in transferrin receptor mRNA expression. The possible role of protein phosphorylation in these mechanisms will be studied. Finally, Al promotion of oxidative damage will be determined in oligodendrocyte cultures. Lipid peroxidation is thought to underlie myelin loss when Al exposure occurs in adults. The proposed studies will be conducted in primary cultures. Specific Aim 2 examines developmental myelination and aging-related myelin loss in vivo. In utero myelination will be studied in pregnant guinea pigs to better model the same developmental period in humans. Al lactate will be given by gavage and compared to Pb, a known myelin toxicant in guinea pigs. Brain, spinal cord and peripheral nerve will be studied. Also, Al lactate will be added to diet of mice to study myelin loss near the end of the lifespan through measures of brain composition and myelin amount and composition. Specific Aim 3 seeks to provide a better context for understanding the public health significance of neurobehavioral changes caused by Al in mice by further characterizing the nature of the effects (changes in hearing, motor coordination and spatial learning) and by identifying common dietary deficiencies that might exacerbate these effects.